Alcohol misuse continues to be a public health problem and identifying effective medications for the treatment of alcohol use disorders remains a high priority for NIAAA (Li , 2006). Given the strong evidence that the nicotinic acetylcholine receptor (nAChR) system is involved in modulating alcohol effects and consumption, this system holds promise as a viable target for medications development for alcohol use disorders. Prior work in this area has been limited due to the lack of suitable and specific nAChR agents for human administration. The recent FDA approval of varenicline, a partial nicotinic agonist, presents an exciting opportunity to further our understanding of the role of nAChRs in human alcohol consumption, and to evaluate whether clinical trial investigations examining the efficacy of varenicline for alcohol use disorders should be pursued. Support for this project comes from a pilot investigation conducted by our group (see Section C.1.1). Using an established alcohol self-administration paradigm (O'Malley et al., 2002) that is sensitive to medication effects on alcohol consumption, we evaluated whether varenicline (2 mg/day) altered reactivity to a fixed low dose of alcohol (.03 g/dl priming drink) and subsequent ad-libitum consumption in heavy drinking smokers and non-smokers. Varenicline attenuated alcohol craving and subjective alcohol effects (e.g., subjective intoxication) in response to the priming drink, robustly reduced alcohol self-administration, and was well tolerated in heavy drinking smokers and non-smokers. These results mirror preclinical studies examining the effect of varenicline on ethanol seeking and consumption (Steensland et al., 2007). Building on this preliminary investigation, our primary goal in the current application is to conduct a dose ranging study of varenicline to determine which doses of varenicline are efficacious for reducing alcohol self- administration behavior, and are safe and well tolerated. Specifically, smokers and non-smokers who meet criteria for alcohol use disorders will be randomized to varenicline (0, 1.0, 2.0 mg/day), titrated to steady state levels over the course of 9 days, participate in our alcohol self-administration laboratory paradigm, and then assessed for 2-weeks following medication discontinuation. We hypothesize that varenicline (1.0, 2.0 mg/day) compared to placebo (0 mg/day) will decrease the number of drinks consumed during the self-administration period, and secondarily, will reduce subjective reactivity (e.g., alcohol craving) to the initial priming dose of alcohol. We also expect that varenicline will be safe and well tolerated during the titration period and in combination with alcohol in both smokers and non-smokers who meet criteria for alcohol use disorders. To our knowledge, this will be the first dose-ranging investigation of varenicline effects on human alcohol consumption. Results will provide important information concerning dose selection for future clinical trial investigations, evidence that the nicotinic system is a viable medications target for alcohol use disorders, and elucidate potential mechanisms for these effects. PUBLIC HEALTH RELEVANCE: Given the strong evidence that the nicotinic acetylcholine receptor (nAChR) system is involved in modulating alcohol effects and consumption, this system holds promise as a viable target for medications development for alcohol use disorders. The recent FDA approval of varenicline, a partial nicotinic agonist, presents an exciting opportunity to further our understanding of the role of nAChRs in human alcohol consumption, and to evaluate whether clinical trial investigations examining the efficacy of varenicline for alcohol use disorders should be pursued. Using a laboratory paradigm, our primary goal in the current application is to conduct a dose-ranging study of varenicline to determine which doses of varenicline are efficacious for reducing alcohol self-administration behavior, and are safe and well tolerated in smokers and non-smokers who meet criteria for alcohol use disorders.